1. Field of the Invention
The present invention relates generally to the fields of developmental and molecular biology. More particularly, it concerns Bright/ARID3a function in the context of cell pluripotency. Specifically, the invention relates to the use inhibitors of Bright to regulate pluripotency, for example, in the context of de-differentiation and re-differentiation of cells.
2. Description of Related Art
Embryonic stem cells (ESCs) are pluripotent and can ultimately lead to the generation of all tissue types. Therefore, these cells have great potential for tissue replacement therapy in degenerative diseases. However, there are several major obstacles to overcome. First, the availability of ESCs is limited and ethically controversial. Second, growth of ESCs is technically challenging and requires feeder layers of other cells. Third, because the molecular mechanisms for controlled differentiation of specific cell types are not clearly delineated, there is risk that pluripotent cells will eventually result in production of unwanted cell types and/or tumor formation if their growth cannot be controlled. Finally, transplantation of tissues is best when major histocompatability antigens are identical and exact tissue matching has not been possible with currently utilized models.
There have been several recent reports that pluripotent cells can be generated from terminally differentiated cells, thereby opening up another possible source for ESCs. Somatic cell fusion technology and incubation of somatic cells with extracts from pluripotent cells have shown limited success, but more promising results have been obtained by focusing on four regulatory factors—Oct3/4, Sox2, c-Myc and Klf4. Yu et al. (2007) used these four genes to successfully reprogram fetal human fibroblasts. Takahashi et al. (2007) achieved similar results with adult human dermal fibroblasts. Nakagawa et al. (2008) was able to reprogram mouse fibroblasts with only Oct3/4, Sox2, and Klf4, thereby obviating concerns over the use of the c-Myc oncogene. Most recently, Hanna et al. (2008) used Oct3/4, Sox2, c-Myc and Klf4 to reprogram non-terminally differentiated mouse B-lymphocytes, although an additional factor was required to reprogram mature lymphocytes.
Despite these successes, the use of four different trangenes to achieve reprogramming has serious limitations. First, these methods are tedious and time consuming, and require introduction through viral vectors which remain in the host cells. Efficiencies are low (<1%), likely because it is not clear what gene dosages are necessary for reprogramming endogenous genes required for pluripotency. Second, the aforementioned concerns over the use of an oncogene will likely present a major hurdle to any in vivo applications in humans. Introduction of pluripotent cells into immunocompromised mouse models typically leads to teratoma formation. And third, once de-differentiated, it may be difficult to re-differentiate cells if their transformation by Oct3/4, Sox2, c-Myc and Klf4 is stable, i.e., not transient or reversible. As such, there remains a need for improved methods of restoring pluripotency in terminally differentiated human cells.